EP1467983B1 - Method for producing thioctic acid - Google Patents

Method for producing thioctic acid Download PDF

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EP1467983B1
EP1467983B1 EP03729427A EP03729427A EP1467983B1 EP 1467983 B1 EP1467983 B1 EP 1467983B1 EP 03729427 A EP03729427 A EP 03729427A EP 03729427 A EP03729427 A EP 03729427A EP 1467983 B1 EP1467983 B1 EP 1467983B1
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general formula
mixtures
racemic
solution
thioctic
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EP1467983A1 (en
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Gunter Laban
Peter Meisel
Gilbert MÜLLER
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Meda Pharma GmbH and Co KG
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Viatris GmbH and Co KG
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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D339/00—Heterocyclic compounds containing rings having two sulfur atoms as the only ring hetero atoms
    • C07D339/02—Five-membered rings
    • C07D339/04—Five-membered rings having the hetero atoms in positions 1 and 2, e.g. lipoic acid

Definitions

  • the invention relates to a process for preparing thioctic acids of the general formula III in the form of the racemate and the R and S enantiomers and mixtures thereof in high yield and purity.
  • Thioctic acid is pharmacologically active and has anti-inflammatory, antinociceptive and cytoprotective properties (EP 0427247).
  • racemic thioctic acid An important medical indication of racemic thioctic acid is the high-dose long-term therapy of diabetic polyneuropathy.
  • Thioctic acid may also gain importance in the control of HIV-1 and HTLV III B virus-related diseases (Baur, A., et al., Klin. Klischr., 1991, 69 , 722, JP Merin et al., FEBS Lett , 394 , 9).
  • the R-enantiomer of thioctic acid is a natural substance found in low concentrations in virtually all animal and plant cells.
  • the R-thioctic acid is of essential importance as a coenzyme in the oxidative decarboxylation of ⁇ -keto carboxylic acids (e.g., pyruvic acid).
  • the R-enantiomer In the case of the pure optical isomers of thioctic acid, the R-enantiomer is predominantly antiphlogistic and the S-enantiomer is predominantly antinociceptive (EP 0427247). Different pharmacokinetic properties of the two enantiomers have also been found (e.g., R. Hermann et al., Eur. J. Pharmaceut. Sci., 1996, 4, 167). Thus, both the synthesis of the racemate and that of the pure enantiomers are of great importance.
  • a known production principle for the thioctic acids of the general formula III consists in the reaction of 6,8-disubstituted octanoic acids or their alkali metal salts and esters of the general formula 1 in which X, Y, R and R 'have the meanings given below and X, Y may be the same or different, with a sulfonation reagent prepared from equimolar amounts of sodium sulfide and sulfur, which by virtue of its stoichiometric Composition commonly referred to as sodium disulfide (Na 2 S 2 ), or in the joint action of sodium sulfide (Na 2 S) and sulfur on the compounds of general formula I (DS Acker and WJ Wayne, J. Am.
  • the compounds of the general formula I can be used both as a racemate and in the form of the R and S enantiomers or mixtures thereof.
  • the procedure is that the compounds of general formula I are added to a solution of the sulfurizing reagent in a solvent such as ethanol or DMF.
  • R H
  • the common addition of sodium sulfide and sulfur to the alkali metal salt of the acid takes place.
  • Both the sulfur introduction to II and the hydrolysis to III require long reaction times (eg AV Rama Rao et al., Synth. Commun. 1987, 17 , 1339: 24 h).
  • the thioctic acids III obtained under the conditions indicated are contaminated by the compounds IV and V, which may be present in the form of the racemates or as R and S enantiomers, in the range of several percent.
  • the object of the invention is therefore to provide an economical production process for the compound III in high purity and yield.
  • This object is achieved by first preparing a sulfide of the general formula VI, M 2 S VI where M is an alkali metal or ammonium ion, to a mixture consisting of suspended sulfur and the solution of a racemic, (R) - or (S) -6,8-disubstituted octanoic acid, the corresponding alkali salts and alkyl esters of general formula I, added and then a sulfite of the general formula VII, M ' 2 SO 3 VII where M 'is an alkali, ammonium or a half alkaline earth metal ion, allowed to act. It is also possible to use mixtures of the compounds of general formula I.
  • the sulfide VI can be added in solid form or in aqueous or aqueous-alcoholic solution.
  • the aqueous-alcoholic solution may be a mixture of water and a lower alcohol having 1 to 3 carbon atoms.
  • the sulfite VII can be added as a solid salt or in aqueous solution.
  • the sulfite of the general formula VII can also be added in each case in part quantities after the addition of the sulfide of the general formula VI and at the beginning or during the alkaline hydrolysis of II to III.
  • Suitable inert, water-miscible solvents for the compounds of the general formula are both polar, protic solvents, such as lower alcohols having 1 to 3 carbon atoms and dipolar aprotic solvents such as dimethylformamide, N-methylpyrrolidone or acetone and nonpolar solvents such as for example, toluene or n-heptane.
  • the specified solvents can also be used as mixtures.
  • the molar ratio 1: VI: sulfur: VII is 1: 1: 1: 0.5 to 1: 1.5: 2: 3, preferably 1: 1.1: 1.5: 1 to 1: 1.1: 1.5: 2
  • the sulfur introduction can be carried out at temperatures of 0 to 100 ° C, preferably in the range of 5 to 90 ° C.
  • reaction times in both the sulfur introduction to II and in the hydrolysis to III are significantly shortened compared to the prior art.
  • the thioctic acids III are obtained in yields of up to more than 80% in very pure form without the compounds IV and V.
  • the pure products can be obtained by the action of sulfites of the general formula VII, optionally in the presence of inert solvents such as cyclohexane or methyl tert-butyl ether, on the crude products dissolved in dilute alkali solutions.
  • inert solvents such as cyclohexane or methyl tert-butyl ether
  • the mixture is cooled to about 50 ° C, the phases are separated, added to the aqueous phase 500 ml of cyclohexane / ethyl acetate (95: 5) and acidified at an internal temperature of 35 to 40 ° C with stirring about 10% hydrochloric acid (pH 1 to 2). After phase separation, the mixture is extracted with a further 200 ml of cyclohexane / ethyl acetate (95: 5).
  • the mixture is heated to an internal temperature of 82 to 84 ° C (reflux) and added dropwise with vigorous stirring for about 2 h, a solution of 13.8 g (0.11 mol) of sodium sulfide hydrate (content: 62% Na 2 S in 80 ml of water and 40 ml of ethanol.
  • the phases are separated, and the cyclohexane phase is added to a solution of 8 g (0.2 mol) of caustic soda in 600 ml of water and stirred the two-phase system for 2 - 3 h intensive at an internal temperature of about 60 ° C.
  • the mixture is cooled to 40 - 50 ° C, the phases are separated and are added to the aqueous phase 300 ml of cyclohexane.
  • the mixture is heated to an internal temperature of 82 to 84 ° C (reflux) and added dropwise with vigorous stirring for about 2 h, a solution of 13.8 g (0.11 mol) of sodium sulfide hydrate (content: 62% Na 2 S) in 80 ml of water and 40 ml of ethanol.
  • the mixture is then stirred for a further 1 h with gentle reflux, cooled to 40 to 50 ° C, added 200 ml of cyclohexane and 300 ml of water, acidified at an internal temperature of 30 to 35 ° C with 10% hydrochloric acid (pH 1 -. 2) and stirred for 15 minutes.
  • the phases are separated, the cyclohexane phase is added to a solution of 8 g (0.2 mol) of sodium hydroxide and 18.9 g (0.15 mol) of sodium sulfite in 600 ml of water and the two-phase system is stirred vigorously for 2 h at an internal temperature of approx 60 ° C. It is cooled to 40 - 50 ° C, the phases are separated and added to the aqueous phase, 300 ml of cyclohexane.
  • the phases are separated, the cyclohexane phase is added to a solution of 8 g (0.2 mol) of sodium hydroxide and 9.5 g (0.075) of sodium sulfite in 600 ml of water and the two-phase system is stirred vigorously for 2 hours at an internal temperature of 68-70 ° C (reflux). It is cooled to 40 - 50 ° C, the phases are separated and added to the aqueous phase, 300 ml of cyclohexane. At 35-40 ° C is acidified with stirring with 10% hydrochloric acid (pH 1-2).
  • the phases are separated, the mixture is extracted with 300 ml of cyclohexane at 35-40 ° C., the combined cyclohexane phases are stirred for 10 minutes with 1 g Diacel 300 BL (filter aid) at 35-40 ° C., filtered and concentrated in vacuo at maximum 40 ° C bath temperature to about 30% of the original volume.
  • the mixture is stirred for 2 - 3 h at 6 - 10 ° C, the crystals washed with cold cyclohexane (2 x 5 ml) and dried at room temperature.

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  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
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Abstract

The invention relates to a method for producing pure racemic, R- or S-thioctic acid or mixtures thereof by reacting 6,8-disubstituted octanoic acid or their salts or esters with sulfides, sulfur or sulfites.

Description

Die Erfindung betrifft ein Verfahren zur Herstellung von Thioctsäuren der allgemeinen Formel III in Form des Racemats sowie der R- und S-Enantiomere und deren Gemische in hoher Ausbeute und Reinheit.The invention relates to a process for preparing thioctic acids of the general formula III in the form of the racemate and the R and S enantiomers and mixtures thereof in high yield and purity.

Wenn im folgenden von Thioctsäure die Rede ist, sind immer sowohl das racemische Gemisch (R,S-Thioctsäure) als auch die enantiomerenreinen Verbindungen (R- und S-Thioctsäure) sowie Mischungen mit beliebigen Gehalten an Enantiomeren zu verstehen.Whenever thioctic acid is mentioned below, it is always understood that both the racemic mixture (R, S-thioctic acid) and the enantiomerically pure compounds (R- and S-thioctic acid) and mixtures with any desired enantiomeric content are to be understood.

Thioctsäure ist pharmakologisch wirksam und weist antiphlogistische, antinociceptive sowie zytoprotektive Eigenschaften auf (EP 0427247).Thioctic acid is pharmacologically active and has anti-inflammatory, antinociceptive and cytoprotective properties (EP 0427247).

Eine wichtige medizinische Indikation der racemischen Thioctsäure ist die hochdosierte Langzeittherapie der diabetischen Polyneuropathie.An important medical indication of racemic thioctic acid is the high-dose long-term therapy of diabetic polyneuropathy.

Thioctsäure kann auch Bedeutung bei der Bekämpfung von durch HIV-1- und HTLV III B-Viren bedingter Krankheiten erlangen (A. Baur et al., Klin. Wochenschr. 1991, 69, 722; J.P. Merin et al., FEBS Lett. 1996, 394, 9).Thioctic acid may also gain importance in the control of HIV-1 and HTLV III B virus-related diseases (Baur, A., et al., Klin. Wochenschr., 1991, 69 , 722, JP Merin et al., FEBS Lett , 394 , 9).

Das R-Enantiomer der Thioctsäure ist ein Naturstoff, der in geringen Konzentrationen in praktisch allen tierischen und pflanzlichen Zellen vorkommt. Die R-Thioctsäure ist als Coenzym bei der oxidativen Decarboxylierung von α-Ketocarbonsäuren (z.B. Brenztraubensäure) von essentieller Bedeutung.The R-enantiomer of thioctic acid is a natural substance found in low concentrations in virtually all animal and plant cells. The R-thioctic acid is of essential importance as a coenzyme in the oxidative decarboxylation of α-keto carboxylic acids (e.g., pyruvic acid).

Bei den reinen optischen Isomeren der Thioctsäure ist das R-Enantiomer vorwiegend antiphlogistisch und das S-Enantiomer vorwiegend antinociceptiv wirksam (EP 0427247). Unterschiedliche pharmakokinetische Eigenschaften der beiden Enantiomere sind ebenfalls festgestellt worden (z.B. R. Hermann et al., Eur. J. Pharmaceut. Sci. 1996, 4, 167). Es ist daher sowohl die Synthese des Racemats als auch die der reinen Enantiomere von großer Wichtigkeit.In the case of the pure optical isomers of thioctic acid, the R-enantiomer is predominantly antiphlogistic and the S-enantiomer is predominantly antinociceptive (EP 0427247). Different pharmacokinetic properties of the two enantiomers have also been found (e.g., R. Hermann et al., Eur. J. Pharmaceut. Sci., 1996, 4, 167). Thus, both the synthesis of the racemate and that of the pure enantiomers are of great importance.

Ein bekanntes Herstellungsprinzip für die Thioctsäuren der allgemeinen Formel lll besteht in der Reaktion von 6,8-disubstituierten Octansäuren bzw. deren Alkalisalzen und Estern der allgemeinen Formel 1, worin X, Y, R und R' die unten angegebene Bedeutung besitzen und X, Y gleich oder verschieden sein können, mit einem aus äquimolaren Mengen Natriumsulfid und Schwefel hergestelltem Schwefelungsreagenz, das auf Grund seiner stöchiometrischen Zusammensetzung häufig als Natriumdisulfid (Na2S2) bezeichnet wird, bzw. in der gemeinsamen Einwirkung von Natriumsulfid (Na2S) und Schwefel auf die Verbindungen der allgemeinen Formel I (D.S. Acker und W.J. Wayne, J. Am. Chem. Soc. 1957, 79, 6483; A.V. Rama Rao et al., Synth. Commun. 1987, 17, 1339; M.H. Brookes et al., J. Chem. Soc. Perkin Trans. I 1988, 9; P.C.B. Page et al., J. Chem. Soc. Perkin Trans I 1990, 1615; A.S. Gopalan et al., J. Chem. Soc. Perkin Trans. I 1990, 1897; J.S. Yadav et al., J. Carbohydrate Chem., 1990, 9, 307; DE 19533881; G. Bringmann et al., Z. Naturforsch. 54b, 655 (1999)).A known production principle for the thioctic acids of the general formula III consists in the reaction of 6,8-disubstituted octanoic acids or their alkali metal salts and esters of the general formula 1 in which X, Y, R and R 'have the meanings given below and X, Y may be the same or different, with a sulfonation reagent prepared from equimolar amounts of sodium sulfide and sulfur, which by virtue of its stoichiometric Composition commonly referred to as sodium disulfide (Na 2 S 2 ), or in the joint action of sodium sulfide (Na 2 S) and sulfur on the compounds of general formula I (DS Acker and WJ Wayne, J. Am. Chem. 1957, 79, 6483; Rama Rao AV, et al, Synth Commun, 1987, 17, 1339;... MH Brookes et al, J. Chem Soc Perkin Trans I, 1988, 9;.... PCB Page et al, J. Chem. Soc. Perkin Trans I 1990, 1615; AS Gopalan et al., J. Chem. Soc. Perkin Trans. I 1990, 1897; JS Yadav et al., J. Carbohydrate Chem., 1990, 9 , 307; DE 19533881, G. Bringmann et al., Z. Naturforsch., 54b, 655 (1999)).

Die Verbindungen der allgemeinen Formel I können dabei sowohl als Racemat als auch in Form der R- sowie S-Enantiomere oder deren Gemische eingesetzt werden. Dabei wird so vorgegangen, daß die Verbindungen der allgemeinen Formel I zu einer Lösung des Schwefelungsreagenzes in einem Lösungsmittel wie Ethanol oder DMF hinzugefügt werden. Im Falle der Säuren der allgemeinen Formel I, R=H, erfolgt die gemeinsame Zugabe von Natriumsulfid und Schwefel zum Alkalisalz der Säure.

Figure imgb0001
I II R = C1-4 -Alkyl X, Y = Cl, Br, OSO2R' III R = H R' = C1-4 -Alkyl, Aryl R = H, K, Na, C1-4 -Alkyl The compounds of the general formula I can be used both as a racemate and in the form of the R and S enantiomers or mixtures thereof. The procedure is that the compounds of general formula I are added to a solution of the sulfurizing reagent in a solvent such as ethanol or DMF. In the case of the acids of general formula I, R = H, the common addition of sodium sulfide and sulfur to the alkali metal salt of the acid takes place.
Figure imgb0001
 I II R = C 1-4 alkyl X, Y = Cl, Br, OSO 2 R ' III R = H R '= C 1-4 alkyl, aryl R = H, K, Na, C 1-4 alkyl

Die im Falle von R = C1-4 -Alkyl zunächst erhaltenen Ester II werden anschließend durch Zusatz von Alkali im homogenen Medium zur Thioctsäure III hydrolysiert. Sowohl bei der Schwefeleinführung zu II als auch bei der Hydrolyse zu III sind lange Reaktionszeiten erforderlich (z.B. A.V. Rama Rao et al., Synth. Commun. 1987, 17, 1339 : 24 h).The esters II initially obtained in the case of R = C 1-4 -alkyl are subsequently hydrolyzed to thioctic acid III by the addition of alkali in the homogeneous medium. Both the sulfur introduction to II and the hydrolysis to III require long reaction times (eg AV Rama Rao et al., Synth. Commun. 1987, 17 , 1339: 24 h).

Die unter den angegebenen Bedingungen erhaltenen Thioctsäuren III sind jedoch durch die Verbindungen IV und V, die in Form der Racemate oder als R- bzw. S-Enantiomere vorliegen können, im Bereich von mehreren Prozent verunreinigt.

Figure imgb0002
However, the thioctic acids III obtained under the conditions indicated are contaminated by the compounds IV and V, which may be present in the form of the racemates or as R and S enantiomers, in the range of several percent.
Figure imgb0002

Da die Verbindungen IV und V sich strukturell von der Thioctsäure lediglich nur durch die Anzahl der Schwefelatome unterscheiden, sind die für wirtschaftliche Trenn- und Reinigungsoperationen wie Destillation und Umkristallisation erforderlichen Unterschiede der physikochemischen Eigenschaften, wie z.B. Flüchtigkeit und Löslichkeit, nur gering. Die nachträgliche Abtrennung der während der Reaktion gebildeten Nebenprodukte IV und V ist extrem aufwendig und somit auf wirtschaftliche Weise nicht möglich.Eine Detektion ist nur durch spezielle analytische Methoden, wie z.B. HPLC, möglich. Daß bei den bisher bekannten Verfahren auch die Verbindungen IV und V gebildet wurden, ist nicht verwunderlich, denn es ist allgemein bekannt, daß bei der Umsetzung von Natriumsulfid (Na2S) mit Schwefel ein Gemisch von Sulfiden (Na2Sx) unterschiedlicher Kettenlänge x entsteht. Dies führt dazu, daß bei der Umsetzung von 6,8-disubstituierten Octansäuren sowie deren Alkalisalzen und Estern mit Natriumsulfid / Schwefel (Molverhältnis 1:1) nicht nur die auf Grund der Stöchiometrie erwartete Thioctsäure gebildet wird (x = 2, Einbau einer S2-Einheit), sondern durch Einbau von "S1" (wenn x = 1) die 5-(2-Thiacyclobutyl)-valeriansäure IV sowie von "S3" (wenn x = 3) die 5-(1,2,3)Trithian-4-yl-pentansäure V neben höheren aliphatischen und cyclischen Polysulfiden gebildet werden.Since compounds IV and V differ structurally from thioctic acid only by the number of sulfur atoms, the differences in physicochemical properties required for economic separation and purification operations such as distillation and recrystallization, such as volatility and solubility, are small. The subsequent separation of the by-products IV and V formed during the reaction is extremely complicated and thus not economically possible. Detection is only possible by special analytical methods, such as HPLC. That in the previously known methods, the compounds IV and V were formed, is not surprising, because it is well known that in the implementation of sodium sulfide (Na 2 S) with sulfur, a mixture of sulfides (Na 2 S x ) of different chain length x arises. As a result, in the reaction of 6,8-disubstituted octanoic acids and their alkali metal salts and esters with sodium sulfide / sulfur (molar ratio 1: 1), not only the thioctic acid expected due to the stoichiometry is formed (x = 2, incorporation of a S 2) Unit), but by incorporating "S 1 " (when x = 1) the 5- (2-thiacyclobutyl) valeric acid IV and "S 3 " (when x = 3) the 5- (1,2,3 ) Trithian-4-yl-pentanoic acid V are formed in addition to higher aliphatic and cyclic polysulfides.

Deshalb wurden die mit der einstufigen Direkteinführung des Schwefels in 6,8-disubstituierte Octansäuren sowie deren Alkalisalze und Ester der allgemeinen Formel verbundenen Qualitätsprobleme häufig dadurch umgangen, indem die rohe Thioctsäure zunächst durch NaBH4 zur 6,8-Dimercapto-octansäure reduziert wurde, die in einer weiteren Stufe zur Thioctsäure oxidiert werden mußte (z.B. DE 19533881).Therefore, the problems associated with the one-step direct introduction of sulfur into 6,8-disubstituted octanoic acids and their alkali salts and esters of the general formula quality problems were often circumvented by the crude thioctic acid was first reduced by NaBH 4 to 6,8-dimercapto-octanoic acid, the had to be oxidized in a further step to thioctic acid (eg DE 19533881).

Dadurch wird jedoch nur die Abreicherung der reduktiv zur 6,8-Dimercapto-octansäure abbaubaren Verbindung V erreicht, nicht jedoch die Entfernung von IV.However, only the depletion of reductively degradable to 6,8-dimercapto-octanoic acid compound V is achieved, but not the removal of IV.

Noch aufwendiger ist die Schwefeleinführung über die Umsetzung der 6,8-disubstituierten Octansäuren und deren Ester mit Thiohamstoff zu den Salzen der 6,8-Bis(amidiniumthio)-octansäure, deren Spaltung zur 6,8-Dimercapto-octansäure und Oxidation zur Thioctsäure (3-Stufen-Verfahren, z.B. F. Balkenhohl und J. Paust, Z. Naturforsch. 54b, 649 (1999); DE 19601787).Even more expensive is the introduction of sulfur via the reaction of 6,8-disubstituted octanoic acids and their esters with thiourea to the salts of 6,8-bis (amidiniumthio) octanoic acid, their cleavage to 6,8-dimercapto-octanoic acid and oxidation to thioctic acid ( Balkenhohl and J. Paust, Z. Naturforsch 54b, 649 (1999), DE 19601787).

Zusammenfassend kann festgestellt werden, daß die beschriebene Arbeitsweise mangelhaft ist und ein wirtschaftliches Verfahren zur Herstellung reiner Thioctsäure der allgemeinen Formel III nicht existiert. Die Bereitstellung von reiner Thioctsäure ist jedoch auch auf Grund der o.g. hochdosierten Langzeittherapie besonders wichtig.In summary, it can be stated that the procedure described is deficient and an economical process for the preparation of pure thioctic acid of the general formula III does not exist. However, the provision of pure thioctic acid is also due to the o.g. high-dose long-term therapy particularly important.

Aufgabe der Erfindung ist es deshalb, ein wirtschaftliches Herstellungsverfahren für die Verbindung III in hoher Reinheit und Ausbeute bereitzustellen.The object of the invention is therefore to provide an economical production process for the compound III in high purity and yield.

Diese Aufgabe wird dadurch gelöst, daß man zuerst ein Sulfid der allgemeinen Formel VI,

        M2S     VI

wobei M ein Alkali- oder Ammoniumion bedeutet, zu einem Gemisch, bestehend aus suspendiertem Schwefel und der Lösung einer racemischen, (R)- oder (S)-6,8-disubstituierten Octansäure, der entsprechenden Alkalisalze sowie Alkylester der allgemeinen Formel I, zudosiert und anschließend ein Sulfit der allgemeinen Formel VII,

        M'2SO3     VII

wobei M' ein Alkali-, Ammonium- oder ein halbes Erdalkaliion bedeutet, einwirken läßt. Es ist dabei auch möglich, Gemische der Verbindungen der allgemeinen Formel I einzusetzen. Das Sulfid VI kann dabei in fester Form oder in wäßriger oder wäßrig-alkoholischer Lösung zudosiert werden. Die wässrig-alkoholische Lösung kann ein Gemisch aus Wasser und einem niederen Alkohol mit 1 bis 3 C-Atomen sein. Das Sulfit VII kann als festes Salz oder in wäßriger Lösung zugegeben werden.This object is achieved by first preparing a sulfide of the general formula VI,

M 2 S VI

where M is an alkali metal or ammonium ion, to a mixture consisting of suspended sulfur and the solution of a racemic, (R) - or (S) -6,8-disubstituted octanoic acid, the corresponding alkali salts and alkyl esters of general formula I, added and then a sulfite of the general formula VII,

M ' 2 SO 3 VII

where M 'is an alkali, ammonium or a half alkaline earth metal ion, allowed to act. It is also possible to use mixtures of the compounds of general formula I. The sulfide VI can be added in solid form or in aqueous or aqueous-alcoholic solution. The aqueous-alcoholic solution may be a mixture of water and a lower alcohol having 1 to 3 carbon atoms. The sulfite VII can be added as a solid salt or in aqueous solution.

Dabei ist es im Falle der Ester der allgemeinen Formel I, R = C 1-4 -Alkyl, auch möglich, das Sulfit der allgemeinen Formel VII zu Beginn oder während der alkalischen Hydrolyse von II zu III zuzugeben. Weiterhin kann das Sulfit der allgemeinen Formel VII auch jeweils in Teilmengen nach der Zugabe des Sulfides der allgemeinen Formel VI sowie zu Beginn oder während der alkalischen Hydrolyse von II zu lll hinzugefügt werden.It is also possible in the case of esters of the general formula I, R = C 1-4 alkyl, to add the sulfite of the general formula VII at the beginning or during the alkaline hydrolysis of II to III. Furthermore, the sulfite of the general formula VII can also be added in each case in part quantities after the addition of the sulfide of the general formula VI and at the beginning or during the alkaline hydrolysis of II to III.

Als inerte, mit Wasser mischbare Lösungsmittel für die Verbindungen der allgemeinen Formel eignen sich sowohl polare, protische Lösungsmittel, wie niedere Alkohole mit 1 bis 3 C-Atomen als auch dipolar-aprotische Lösungsmittel wie beispielsweise Dimethylformamid, N-Methylpyrrolidon oder Aceton sowie unpolare Lösungsmittel wie beispielsweise Toluol oder n-Heptan. Die angegebenen Lösungsmittel können auch als Gemische eingesetzt werden.Suitable inert, water-miscible solvents for the compounds of the general formula are both polar, protic solvents, such as lower alcohols having 1 to 3 carbon atoms and dipolar aprotic solvents such as dimethylformamide, N-methylpyrrolidone or acetone and nonpolar solvents such as for example, toluene or n-heptane. The specified solvents can also be used as mixtures.

Es ist auch möglich, Mischungen von Wasser sowohl mit den reinen Lösungsmitteln als auch mit den Lösungsmittelgemischen zu verwenden.It is also possible to use mixtures of water with both the pure solvents and with the solvent mixtures.

Das Molverhältnis 1 : VI : Schwefel : VII beträgt dabei 1 : 1 : 1 : 0.5 bis 1 : 1.5 : 2 : 3, vorzugsweise
1 : 1.1 : 1.5 : 1 bis 1 : 1,1 : 1,5 : 2The molar ratio 1: VI: sulfur: VII is 1: 1: 1: 0.5 to 1: 1.5: 2: 3, preferably
1: 1.1: 1.5: 1 to 1: 1.1: 1.5: 2

Die Schwefeleinführung kann bei Temperaturen von 0 bis 100°C, vorzugsweise im Bereich von 5 bis 90 °C,durchgeführt werden.The sulfur introduction can be carried out at temperatures of 0 to 100 ° C, preferably in the range of 5 to 90 ° C.

In speziellen Fällen, wie beispielsweise beim Einsatz der (S)- sowie (R)-8-Chlor-6-sulfonyloxy-octansäuren, der entsprechenden Alkalisalze sowie Alkylester der allgemeinen Formel (X = Cl, Br, Y = OSO2R') ist es notwendig, zur Vermeidung von Racemisierungen die Reaktionstemperatur abzustufen, indem die Sulfid-Zugabe bei 30 - 50 °C, vorzugsweise 35 - 45 °C, durchgeführt wird und erst danach die Reaktionstemperatur erhöht wird.In special cases, such as, for example, when using the (S) - and (R) -8-chloro-6-sulfonyloxy-octanoic acids, the corresponding alkali salts and alkyl esters of the general formula (X =Cl, Br, Y = OSO 2 R ') It is necessary to scale the reaction temperature to avoid racemizations by the sulfide addition at 30 - 50 ° C, preferably 35 - 45 ° C, performed and only then the reaction temperature is increased.

Die alkalische Hydrolyse von II zu III erfolgt schonend im Zweiphasensystem Cyclohexan bzw. Methyl-tert.butylether / verdünnte Alkalilauge bei Temperaturen von 30 bis 90 °C, üblicherweise mit Reaktionszeiten < 5 h.The alkaline hydrolysis of II to III takes place gently in the two-phase system cyclohexane or methyl tert-butyl ether / dilute alkali solution at temperatures of 30 to 90 ° C, usually with reaction times <5 h.

Die Reaktionszeiten sowohl bei der Schwefeleinführung zu II als auch bei der Hydrolyse zu III sind gegenüber dem Stand der Technik wesentlich verkürzt.The reaction times in both the sulfur introduction to II and in the hydrolysis to III are significantly shortened compared to the prior art.

Die Thioctsäuren III werden in Abhängigkeit vom eingesetzten Octansäurederivat I in Ausbeuten bis über 80 % in sehr reiner Form ohne die Verbindungen IV und V erhalten.Depending on the octanoic acid derivative I used, the thioctic acids III are obtained in yields of up to more than 80% in very pure form without the compounds IV and V.

In einer besonderen Ausführungsform der Erfindung ist es auch möglich, bei ansonsten erfindungsgemäßer Arbeitsweise auf die Zugabe des Sulfits der allgemeinen Formel VII während der Umsetzung von I zu II bzw. zu III zu verzichten und die insbesonders stark mit der Verbindung V verunreinigten Rohprodukte zunächst zu isolieren.In a particular embodiment of the invention, it is also possible to dispense with otherwise inventive operation on the addition of the sulfite of the general formula VII during the reaction of I to II or III and to isolate the particularly heavily contaminated with the compound V crude products first ,

Die Reinprodukte lassen sich durch Einwirkung von Sulfiten der allgemeinen Formel VII, gegebenenfalls in Gegenwart von inerten Lösungsmitteln wie Cyclohexan oder Methyl-tert.butylether, auf die in verdünnten Alkalilaugen gelösten Rohprodukte erhalten.The pure products can be obtained by the action of sulfites of the general formula VII, optionally in the presence of inert solvents such as cyclohexane or methyl tert-butyl ether, on the crude products dissolved in dilute alkali solutions.

Im folgenden wird die Erfindung anhand von Beispielen näher erläutert, ohne sie jedoch einzuschränken.In the following the invention will be explained in more detail by means of examples, without, however, restricting them.

Beispiel 1example 1

Man gibt eine Lösung von 4,0 g (0,1 Mol) Natriumhydroxid in 10 ml Wasser zu 100 ml Ethanol (96 %) und fügt nacheinander 21,3 g (0,1 Mol) rac. 6,8-Dichloroctansäure (D.S. Acker und W.J. Wayne, J. Amer Chem. Soc. 1957, 79, 6483) und 4,8 g (0,15 Mol) Schwefel unter Rühren hinzu. Das Gemisch wird zum leichten Rückfluß erhitzt (Innentemperatur 78 - 80 °C). Unter Rühren tropft man während ca.2 h bei leichtem Rückfluß eine Lösung von 13,8 g (0,11 Mol) Natriumsulfid-Hydrat (Gehalt: 62 % Na2S), gelöst in einem Gemisch von 70 ml Wasser und 40 ml Ethanol (96 %), zu.A solution of 4.0 g (0.1 mol) of sodium hydroxide in 10 ml of water is added to 100 ml of ethanol (96%) and successively added 21.3 g (0.1 mol) of rac. 6,8-dichlorooctanoic acid (DS Acker and WJ Wayne, J. Amer. Chem. Soc. 1957, 79, 6483) and 4.8 g (0.15 mol) of sulfur with stirring. The mixture is heated to gentle reflux (internal temperature 78-80 ° C). While stirring, a solution of 13.8 g (0.11 mol) of sodium sulfide hydrate (content: 62% Na 2 S), dissolved in a mixture of 70 ml of water and 40 ml of ethanol, is added dropwise with stirring for about 2 h with gentle reflux (96%), too.

Anschließend läßt man eine Lösung von 18,9 g (0,15 Mol) Natriumsulfit in 75 ml Wasser zulaufen und rührt 1 h bei einer Innentemperatur von ca. 80 °C nach. Man kühlt auf ca. 50 °C ab und fügt 600 ml Wasser sowie 250 ml eines Gemisches Cyclohexan / Ethylacetat 4 : 1 hinzu. Bei 35 - 40 °C wird unter Rühren mit 10 %iger Salzsäure angesäuert (pH 1). Man trennt
die Phasen, extrahiert 2 x mit je 100 ml Cyclohexan / Ethylacetat 4 : 1 bei 35 - 40 °C nach und engt die vereinigten organischen Phasen im Vakuum schonend (Badtemperatur bis 40° C) ein. Man kühlt unter Rühren auf 0 bis 5 °C (Beginn der Kristallisation) und anschließend 2 bis 3 h bei -5 bis -10 °C. Nach dem Waschen mit kaltem Cyclohexan und Trocknen (30 °C) erhält man 17,7 bis 18,4 g (86 - 89 % d.Th.) reine R,S-Thioctsäure.
Fp 61 °C (aus Cyclohexan /Ethylacetat 4:1)Then allowed to run a solution of 18.9 g (0.15 mol) of sodium sulfite in 75 ml of water and stirred for 1 h at an internal temperature of about 80 ° C after. It is cooled to about 50 ° C and added to 600 ml of water and 250 ml of a mixture of cyclohexane / ethyl acetate 4: 1 added. At 35-40 ° C is acidified with 10% hydrochloric acid with stirring (pH 1). You part
the phases, extracted 2 x with 100 ml of cyclohexane / ethyl acetate 4: 1 at 35- 40 ° C and concentrated the combined organic phases in a vacuum gently (bath temperature to 40 ° C). The mixture is cooled with stirring to 0 to 5 ° C (beginning of crystallization) and then for 2 to 3 h at -5 to -10 ° C. After washing with cold cyclohexane and drying (30 ° C) to obtain 17.7 to 18.4 g (86 - 89% of theory) of pure R, S-thioctic acid.
Mp 61 ° C (from cyclohexane / ethyl acetate 4: 1)

Beispiel 2Example 2

Man fügt unter Rühren 24,1g (0,1 Mol) 6,8-Dichloroctansäureethylester und anschließend 4,8 g (0,15 Mol) Schwefel zu einem Gemisch von 50 ml Ethanol und 50 ml n-Propanol.24.1 g (0.1 mol) of ethyl 6,8-dichlorooctanoate and then 4.8 g (0.15 mol) of sulfur are added with stirring to a mixture of 50 ml of ethanol and 50 ml of n-propanol.

Nach dem Erwärmen auf eine Innentemperatur von 82 bis 84°C (Rückfluß) tropft man unter intensivem Rühren während 2 bis 2,5 h eine Lösung von 13,8 g (0,11 Mol) Natriumsulfid-Hydrat (Gehalt:62 % Na2S) in 80 ml Wasser und 40 ml Ethanol zu.After heating to an internal temperature of 82 to 84 ° C (reflux) is added dropwise with vigorous stirring for 2 to 2.5 h, a solution of 13.8 g (0.11 mol) of sodium sulfide hydrate (content: 62% Na 2 S) in 80 ml of water and 40 ml of ethanol.

Dann gibt man eine Lösung von 18,9 g (0,15 Mol) Natriumsulfit in 75 ml Wasser zügig zu und erhitzt noch 1 h bei leichtem Rückfluß.Man kühlt auf etwa 50°C ab, fügt 200 ml Cyclohexan und 300 ml Wasser hinzu, stellt bei einer Innentemperatur von 30 bis 35°C unter Rühren mit 10%iger Salzsäure auf einen pH-Wert von ca. 1 und rührt ca. 15 min nach. Man trennt die Phasen, fügt die Cyclohexan-Phase zu einer Lösung von 8 g (0,2 Mol) Natriumhydroxid in 600 ml Wasser und rührt das Zweiphasensystem ca. 4h intensiv bei einer Innentemperatur von ca. 70°C (leichter Rückfluß).Then, a solution of 18.9 g (0.15 mol) of sodium sulfite in 75 ml of water rapidly and heated for 1 h at a gentle Rückfluß.Man cooled to about 50 ° C, add 200 ml of cyclohexane and 300 ml of water , At an internal temperature of 30 to 35 ° C with stirring with 10% hydrochloric acid to a pH of about 1 and stirred for about 15 minutes after. The phases are separated, the cyclohexane phase is added to a solution of 8 g (0.2 mol) of sodium hydroxide in 600 ml of water, and the two-phase system is stirred vigorously for about 4 hours at an internal temperature of about 70 ° C (gentle reflux).

Man kühlt auf ca. 50°C ab, trennt die Phasen, fügt zur wäßrigen Phase 500 ml Cyclohexan/Ethylacetat (95:5) hinzu und säuert bei einer Innentemperatur von 35 bis 40°C unter Rühren mit
ca. 10%iger Salzsäure an (pH 1 bis 2). Nach der Phasentrennung extrahiert man mit weiteren 200 ml Cyclohexan/Ethylacetat (95:5) nach.The mixture is cooled to about 50 ° C, the phases are separated, added to the aqueous phase 500 ml of cyclohexane / ethyl acetate (95: 5) and acidified at an internal temperature of 35 to 40 ° C with stirring
about 10% hydrochloric acid (pH 1 to 2). After phase separation, the mixture is extracted with a further 200 ml of cyclohexane / ethyl acetate (95: 5).

Die vereinigten organischen Phasen werden mit 1g Diacel 300 BL (Filtrierhilfsmittel) ca. 10 min bei ca. 30°C gerührt und nach dem Filtrieren im Vakuum bei maximal 40°C Badtemperatur auf ca. 200 ml eingeengt. Man läßt unter Rühren bei -5 bis -10°C 4 bis 6 h kristallisieren. Nach dem Waschen mit kaltem Cyclohexan und Trocknen bei 30°C erhält man 14,6 bis 15,7 g (71 bis 76% d.Th.) reine R,S-Thioctsäure.
Fp 61 °C (aus Cyclohexan/Ethylacetat)The combined organic phases are stirred with 1 g Diacel 300 BL (filter aid) for about 10 min at about 30 ° C and concentrated after filtration in vacuo at a maximum of 40 ° C bath temperature to about 200 ml. The mixture is allowed to crystallize with stirring at -5 to -10 ° C for 4 to 6 hours. After washing with cold cyclohexane and drying at 30 ° C., 14.6 to 15.7 g (71 to 76% of theory) of pure R, S-thioctic acid are obtained.
Mp 61 ° C (from cyclohexane / ethyl acetate)

Beispiel 3Example 3

Zu einer Lösung von 22,7 g (0,1 Mol) (S)-6,8-Dichloroctansäuremethylester (DE 19533881) in einem Gemisch von 50 ml Ethanol und 50 ml n-Propanol fügt man unter Rühren 4,8 g (0,15 Mol) Schwefel hinzu.To a solution of 22.7 g (0.1 mol) of (S) -6,8-Dichloroctansäuremethylester (DE 19533881) in a mixture of 50 ml of ethanol and 50 ml of n-propanol is added with stirring 4.8 g (0 , 15 moles) of sulfur.

Man erwärmt auf eine Innentemperatur von 82 bis 84 °C (Rückfluß) und tropft unter intensivem Rühren während ca. 2 h eine Lösung von 13,8 g (0,11 Mol) Natriumsulfid-Hydrat (Gehalt: 62 % Na2S in 80 ml Wasser und 40 ml Ethanolzu. Dann gibt man eine Lösung von 18,9 g (0,15 Mol) Natriumsulfit in 75 ml Wasser zügig zu, rührt noch 1 h bei leichtem Rückfluß nach, kühlt auf 40 - 50 °C ab, fügt 200 ml Methyl-tert.butylether (MTBE) und 300 ml Wasser zu, säuert bei einer Innentemperatur von 30 - 35 °C mit 10 %iger Salzsäure an (pH 1-2) und rührt 15 min nach. Man trennt die Phasen, fügt die MTBE-Phase zu einer Lösung von 8 g (0,2 Mol) Ätznatron in 600 ml Wasser und rührt das Zweiphasensystem 2 - 3 h intensiv bei einer Innentemperatur von ca. 55 °C (Rückfluß). Man kühlt auf 40 - 50 °C ab, trennt die Phasen und fügt zur wäßrigen Phase 300 ml Cyclohexan hinzu.The mixture is heated to an internal temperature of 82 to 84 ° C (reflux) and added dropwise with vigorous stirring for about 2 h, a solution of 13.8 g (0.11 mol) of sodium sulfide hydrate (content: 62% Na 2 S in 80 ml of water and 40 ml of ethanol. Then a solution of 18.9 g (0.15 mol) of sodium sulphite in 75 ml of water is added rapidly, the mixture is stirred for a further 1 hour at a gentle reflux, cooled to 40-50.degree 200 ml of methyl tert-butyl ether (MTBE) and 300 ml of water, acidified with 10% hydrochloric acid at an internal temperature of 30-35 ° C (pH 1-2) and stirred for 15 min., The phases are separated, added the MTBE phase to a solution of 8 g (0.2 mol) of caustic soda in 600 ml of water and the two-phase system for 2 - 3 h intensively stirred at an internal temperature of about 55 ° C. (reflux) is cooled to 40-50 ° C, separates the phases and adds to the aqueous phase 300 ml of cyclohexane.

Bei 35 - 40 °C wird unter Rühren mit 10 %iger Salzsäure angesäuert (pH 1-2). Man trennt die Phasen, extrahiert mit 300 ml Cyclohexan bei 35 - 40 °C nach, rührt die vereinigten Cyclohexan-Phasen 10 min mit 1 g Diacel 300 BL (Filtrierhilfsmittel) bei 35 bis 40°C aus, filtriert und engt im Vacuum bei maximal 35 °C auf ca. 30% des ursprünglichen Volumens ein. Man rührt 2 bis 3 h bei 6 - 10 °C, wäscht das Kristallisat mit kaltem Cyclohexan (2 x 5 ml) und trocknet bei Raumtemperatur.
Ausbeute: 15,2 bis 16,3 g (74 - 79 % d. Th.) reine R-Thioctsäure.
Fp 49 - 50 °C (aus Cyclohexan)At 35-40 ° C is acidified with stirring with 10% hydrochloric acid (pH 1-2). The phases are separated, extracted with 300 ml of cyclohexane at 35-40 ° C, the combined cyclohexane phases for 10 min with 1 g of Diacel 300 BL (filter aid) at 35 to 40 ° C, filtered and concentrated in vacuo at maximum 35 ° C to about 30% of the original volume. The mixture is stirred for 2 to 3 h at 6 - 10 ° C, the crystals washed with cold cyclohexane (2 x 5 ml) and dried at room temperature.
Yield: 15.2 to 16.3 g (74-79% of theory) of pure R-thioctic acid.
Mp 49-50 ° C (from cyclohexane)

Beispiel 4Example 4

Eine Lösung von 28,7 g (0,1 Mol) (S)-8-Chlor-6-mesyloxy-octansäuremethylester (DE 19533881) in Toluol (66 %ige Lösung, 43,5 g) gibt man zu 50 ml Ethanol und 50 ml n-Propanol und fügt unter Rühren 4,8 g (0,15 Mol) Schwefel hinzu,
erwärmt auf eine Innentemperatur von 40 - 42 °C und tropft unter intensivem Rühren während 1 h eine Lösung von 13,8 g (0,11 Mol) Natriumsulfid-Hydrat (Gehalt: 62 % Na2S) in 80 ml Wasser und 40 ml Ethanolzu. Man
erwärmt zum Rückfluß (80 bis 84°C), tropft während 1 h eine Lösung von 18,9 g (0,15 Mol) Natriumsulfit in 75 ml Wasser zu und rührt 1 h unter Rückfluß nach.Anschließend kühlt man auf 40 - 50 °C ab, fügt 200 ml Cyclohexan und 300 ml Wasser zu, säuert bei einer Innentemperatur von 30 - 35 °C mit 10 %iger Salzsäure an (pH 1-2) und rührt 15 min nach.A solution of 28.7 g (0.1 mol) of (S) -8-chloro-6-mesyloxy-octanoic acid methyl ester (DE 19533881) in toluene (66% solution, 43.5 g) is added to 50 ml of ethanol and Add 50 ml of n-propanol and add, with stirring, 4.8 g (0.15 mol) of sulfur,
heated to an internal temperature of 40-42 ° C and added dropwise with vigorous stirring for 1 h, a solution of 13.8 g (0.11 mol) of sodium sulfide hydrate (content: 62% Na 2 S) in 80 ml of water and 40 ml Ethanolzu. you
heated to reflux (80 to 84 ° C), added dropwise for 1 h, a solution of 18.9 g (0.15 mol) of sodium sulfite in 75 ml of water and stirred for 1 h under reflux nach.Anschließend is cooled to 40 - 50 ° C, adds 200 ml of cyclohexane and 300 ml of water, acidified at an internal temperature of 30-35 ° C with 10% hydrochloric acid (pH 1-2) and stirred for 15 min after.

Man trennt die Phasen, fügt die Cyclohexan-Phase zu einer Lösung von 8 g (0,2 Mol) Ätznatron
in 600 ml Wasser hinzu und rührt das Zweiphasensystem 2 - 3 h intensiv bei einer Innentemperatur von ca. 60 °C. Man kühlt auf 40 - 50 °C ab, trennt die Phasen und gibt zur wäßrigen Phase 300 ml Cyclohexan.The phases are separated, and the cyclohexane phase is added to a solution of 8 g (0.2 mol) of caustic soda
in 600 ml of water and stirred the two-phase system for 2 - 3 h intensive at an internal temperature of about 60 ° C. The mixture is cooled to 40 - 50 ° C, the phases are separated and are added to the aqueous phase 300 ml of cyclohexane.

Bei 35 - 40 °C wird unter Rühren mit 10 %iger Salzsäure angesäuert (pH 1-2). Man trennt die Phasen, extrahiert mit 300 ml Cyclohexan bei 35 - 40 °C nach, rührt die vereinigten Cyclohexan-Phasen 10 min mit 1 g Diacel 300 BL (Filtrierhilfsmittel) aus, filtriert und engt im Vakuum bis zu einer Badtemperatur von 40°C auf ca. 30% des ursprünglichen Volumens ein. Man rührt 2 bis 3 h bei 5 - 10 °C, wäscht das Kristallisat mit kaltem Cyclohexan (2 x 5 ml) und trocknet bei Raumtemperatur.
Ausbeute: 15,2 bis 16,3 g (-74 bis 79 % d. Th.) reine R-Thioctsäure.
Fp 49 - 50 °C (aus Cyclohexan)At 35-40 ° C is acidified with stirring with 10% hydrochloric acid (pH 1-2). The phases are separated, the mixture is extracted with 300 ml of cyclohexane at 35-40 ° C., the combined cyclohexane phases are stirred for 10 minutes with 1 g of Diacel 300 BL (filter aid), filtered and concentrated under reduced pressure up to a bath temperature of 40 ° C. to about 30% of the original volume. The mixture is stirred for 2 to 3 h at 5 - 10 ° C, the crystals washed with cold cyclohexane (2 x 5 ml) and dried at room temperature.
Yield: 15.2 to 16.3 g (-74 to 79% of theory) of pure R-thioctic acid.
Mp 49-50 ° C (from cyclohexane)

Beispiel 5Example 5

Zu einer Lösung von 22,7 g (0,1 Mol) (S)-6,8-Dichloroctansäuremethylester (DE 19533881) in einem Gemisch von 50 ml Ethanol und 50 ml n-Propanol fügt man unter Rühren 4,8 g (0,15 Mol) Schwefel hinzu.To a solution of 22.7 g (0.1 mol) of (S) -6,8-Dichloroctansäuremethylester (DE 19533881) in a mixture of 50 ml of ethanol and 50 ml of n-propanol is added with stirring 4.8 g (0 , 15 moles) of sulfur.

Man erwärmt auf eine Innentemperatur von 82 bis 84 °C (Rückfluß) und tropft unter intensivem Rühren während ca. 2 h eine Lösung von 13,8 g (0,11 Mol) Natriumsulfid-Hydrat (Gehalt:62% Na2S) in 80 ml Wasser und 40 ml Ethanol zu. Dann rührt man noch 1 h bei leichtem Rückfluß nach, kühlt auf 40 bis 50°C ab, fügt 200 ml Cyclohexan und 300 ml Wasser zu , säuert bei einer Innentemperatur von 30 bis 35°C mit 10%iger Salzsäure an (pH 1 -2) und rührt 15 min nach. Man trennt die Phasen, fügt die Cyclohexan-Phase zu einer Lösung von 8 g (0,2 Mol) Natriumhydroxid und 18,9 g (0,15Mol) Natriumsulfit in 600 ml Wasser und rührt das Zweiphasensystem 2 h intensiv bei einer Innentemperatur von ca. 60°C. Man kühlt auf 40 - 50°C ab, trennt die Phasen und fügt zur wäßrigen Phase 300 ml Cyclohexan hinzu.The mixture is heated to an internal temperature of 82 to 84 ° C (reflux) and added dropwise with vigorous stirring for about 2 h, a solution of 13.8 g (0.11 mol) of sodium sulfide hydrate (content: 62% Na 2 S) in 80 ml of water and 40 ml of ethanol. The mixture is then stirred for a further 1 h with gentle reflux, cooled to 40 to 50 ° C, added 200 ml of cyclohexane and 300 ml of water, acidified at an internal temperature of 30 to 35 ° C with 10% hydrochloric acid (pH 1 -. 2) and stirred for 15 minutes. The phases are separated, the cyclohexane phase is added to a solution of 8 g (0.2 mol) of sodium hydroxide and 18.9 g (0.15 mol) of sodium sulfite in 600 ml of water and the two-phase system is stirred vigorously for 2 h at an internal temperature of approx 60 ° C. It is cooled to 40 - 50 ° C, the phases are separated and added to the aqueous phase, 300 ml of cyclohexane.

Bei 35 - 40°C wird unter Rühren mit 10%iger Salzsäure angesäuert (pH 1-2). Man trennt die Phasen, extrahiert mit 300 ml Cyclohexan bei 35 - 40°C nach, rührt die vereinigten Cyclohexan-Phasen 10 min mit 1 g Diacel 300 BL (Filtrierhilfsmittel) bei 35 - 40°C aus, filtriert und engt im Vakuum bei maximal 40°C Badtemperatur auf ca. 30% des ursprünglichen Volumens ein. Man rührt 2 - 3 h bei 5 - 10°C, wäscht das Kristallisat mit kaltem Cyclohexan (2 x 5 ml) und trocknet bei Raumtemperatur.
Ausbeute: 14,4 bis 15,2 g (70 bis 74% d.Th.) reine R-Thioctsäure
Fp 49 - 50°C (aus Cyclohexan)At 35-40 ° C is acidified with stirring with 10% hydrochloric acid (pH 1-2). The phases are separated, the mixture is extracted with 300 ml of cyclohexane at 35-40 ° C., the combined cyclohexane phases are stirred for 10 minutes with 1 g Diacel 300 BL (filter aid) at 35-40 ° C., filtered and concentrated in vacuo at maximum 40 ° C bath temperature to about 30% of the original volume. The mixture is stirred for 2 - 3 h at 5 - 10 ° C, the crystals washed with cold cyclohexane (2 x 5 ml) and dried at room temperature.
Yield: 14.4 to 15.2 g (70 to 74% of theory) of pure R-thioctic acid
Mp 49-50 ° C (from cyclohexane)

Beispiel 6Example 6

Zu einer Lösung von 22,7 g (0,1 Mol) (S)-6,8-Dichloroctansäuremethylester (DE 19533881) in einem Gemisch von 50 ml Ethanol und 50 ml n-Propanol fügt man unter Rühren 4,8 g (0,15 Mol) Schwefel hinzu. Man erwärmt auf eine Innentemperatur von 82 bis 84 °C (Rückfluß), tropft unter intensivem Rühren während ca. 2 h eine Lösung von 13,8 g (0,11 Mol)To a solution of 22.7 g (0.1 mol) of (S) -6,8-Dichloroctansäuremethylester (DE 19533881) in a mixture of 50 ml of ethanol and 50 ml of n-propanol is added with stirring 4.8 g (0 , 15 moles) of sulfur. The mixture is heated to an internal temperature of 82 to 84 ° C (reflux), added dropwise with vigorous stirring for about 2 h, a solution of 13.8 g (0.11 mol)

Natriumsulfid-Hydrat (Gehalt: 62% Na2S) in 80 ml Wasser und 40 ml Ethanol zu und fügt eine
Lösung von 9,5 g (0,075 Mol) Natriumsulfit in 40 ml Wasser hinzu. Dann rührt man noch 1 h bei
leichtem Rückfluß nach, kühlt auf 40 bis 50°C ab, fügt 200 ml Cyclohexan und 300 ml Wasser zu und säuert bei einer Innentemperatur von 30 bis 35°C mit 10%iger Salzsäure an (pH 1-2). Man trennt die Phasen, fügt die Cyclohexan-Phase zu einer Lösung von 8 g (0,2 Mol) Natriumhydroxid und 9,5 g (0,075) Natriumsulfit in 600 ml Wasser und rührt das Zweiphasensystem 2 h intensiv bei einer Innentemperatur von 68 - 70°C (Rückfluß).
Man kühlt auf 40 - 50°C ab,trennt die Phasen und fügt zur wäßrigen Phase 300 ml Cyclohexan hinzu. Bei 35 - 40°C wird unter Rühren mit 10%iger Salzsäure angesäuert (pH 1-2). Man trennt die Phasen, extrahiert mit 300 ml Cyclohexan bei 35 - 40°C nach, rührt die vereinigten Cyclohexan-Phasen 10 min mit 1 g Diacel 300 BL (Filtrierhilfsmittel) bei 35 - 40°C aus, filtriert und engt im Vakuum bei maximal 40°C Badtemperatur auf ca. 30% des usprünglichen Volumens ein. Man rührt 2 - 3 h bei 6 - 10°C, wäscht das Kristallisat mit kaltem Cyclohexan (2 x 5 ml) und trocknet bei Raumtemperatur.Sodium sulfide hydrate (content: 62% Na 2 S) in 80 ml of water and 40 ml of ethanol and adds one
Solution of 9.5 g (0.075 mol) of sodium sulfite in 40 ml of water. Then it is stirred for 1 h
After slight reflux, cooled to 40 to 50 ° C, adds 200 ml of cyclohexane and 300 ml of water and acidified at an internal temperature of 30 to 35 ° C with 10% hydrochloric acid (pH 1-2). The phases are separated, the cyclohexane phase is added to a solution of 8 g (0.2 mol) of sodium hydroxide and 9.5 g (0.075) of sodium sulfite in 600 ml of water and the two-phase system is stirred vigorously for 2 hours at an internal temperature of 68-70 ° C (reflux).
It is cooled to 40 - 50 ° C, the phases are separated and added to the aqueous phase, 300 ml of cyclohexane. At 35-40 ° C is acidified with stirring with 10% hydrochloric acid (pH 1-2). The phases are separated, the mixture is extracted with 300 ml of cyclohexane at 35-40 ° C., the combined cyclohexane phases are stirred for 10 minutes with 1 g Diacel 300 BL (filter aid) at 35-40 ° C., filtered and concentrated in vacuo at maximum 40 ° C bath temperature to about 30% of the original volume. The mixture is stirred for 2 - 3 h at 6 - 10 ° C, the crystals washed with cold cyclohexane (2 x 5 ml) and dried at room temperature.

Ausbeute: 15,0 bis 16,1 g (73 bis 78% d.Th.) reine R-ThioctsäureYield: 15.0 to 16.1 g (73 to 78% of theory) of pure R-thioctic acid

Beispiel 7Example 7 Reinigung von roher ThioctsäurePurification of crude thioctic acid

5,1 g rohe R-Thioctsäure (Gehalt V: 14%) und 4 g Natriumsulfit wurden in verdünnte Natronlauge (1 g NaOH gelöst in 150 ml Wasser) eingetragen. Die Lösung wurde 3 h bei einer Innentemperatur von 60 - 62°C gerührt. Nach dem Abkühlen wurden 75 ml Cyclohexan hinzugefügt und bei 35 - 40°C unter Rühren mit verdünnter Salzsäure sauer gestellt (pH 1 -2). Nach der Phasentrennung wurde mit 75 ml Cyclohexan bei 35 bis 40°C nachextrahiert.5.1 g of crude R-thioctic acid (content V: 14%) and 4 g of sodium sulfite were introduced into dilute sodium hydroxide solution (1 g of NaOH dissolved in 150 ml of water). The solution was stirred for 3 hours at an internal temperature of 60-62 ° C. After cooling, 75 ml of cyclohexane were added and acidified at 35-40 ° C while stirring with dilute hydrochloric acid (pH 1 -2). After phase separation, it was back-extracted with 75 ml of cyclohexane at 35 to 40 ° C.

Die vereinigten Extrakte wurden im Vakuum bei einer maximalen Badtemperatur von 40°C auf ca. 1/4 des Volumens eingeengt. Die Lösung wurde 2 -3 h bei 5 -10°C gerührt, das Kristallisat mit kaltem Cyclohexan gewaschen und bei Raumtemperatur getrocknet.
Ausbeute: 4,1 g reine R-Thioctsäure
Fp 50 bis 51°CThe combined extracts were concentrated in vacuo at a maximum bath temperature of 40 ° C to about 1/4 of the volume. The solution was stirred for 2 -3 h at 5 -10 ° C, the crystals washed with cold cyclohexane and dried at room temperature.
Yield: 4.1 g of pure R-thioctic acid
Mp 50 to 51 ° C

Claims (8)

  1. Method for producing racemic, R- or S-thioctic acid or mixtures thereof of the general formula III, characterized in that the solution of a sulphide of the general formula VI is metered into a mixture consisting of suspended sulphur and a solution of a racemic, (R)- or (S)-6,8-disubstituted octanoic acid, the corresponding alkali metal salts, alkyl esters and mixtures of the general formula I, in which X, Y, R and R' have the meanings stated below, and then, optionally during or after the hydrolysis of an ester II formed as an intermediate, a sulphite of the general formula VII is allowed to act.
    Figure imgb0004
     X, Y = Cl, Br, OSO2R' II R = C1-4-alkyl R' = C1-4-alkyl, aryl III R = H R = H, K, Na, C1-4-alkyl M2S M'2SO3 VI VII M =K, Na, NH4 M' = K, Na, NH4, Mg/2, Ca/2, Ba/2
  2. Method according to Claim 1, characterized in that the molar ratio I : VI : sulphur : VII is 1 : 1 : 1 : 0.5 to 1 : 1.5 : 2 : 3, preferably 1 : 1.1 : 1.5 : 1 to 1 : 1.1 : 1.5 : 2.
  3. Method according to Claim 1, characterized in that, with the use of the racemic, (R)- or (S)-6,8-disubstituted octanoic esters or mixtures thereof of the general formula I (R = C1-4-alkyl), the initially formed racemic, R- or S-thioctic ester of the general formula II is hydrolysed to give racemic, R- or S-thioctic acid or mixtures thereof of the general formula III.
  4. Method according to Claim 1, characterized in that the sulphide of the general formula VI is metered in in the form of an aqueous or aqueous alcoholic solution.
  5. Method according to Claim 1, characterized in that polar protic solvents, dipolar aprotic solvents, nonpolar solvents, mixtures of said solvents and mixtures with water are used as solvents for the compounds of the general formula I.
  6. Method according to Claim 1, characterized in that the sulphite of the general formula VII is added as a solid salt or in the form of an aqueous solution.
  7. Method for hydrolysing crude racemic, R- or S-thioctic esters of the general formula II in the two-phase system to give pure racemic R- or S-thioctic acid or mixtures thereof in the presence of sulphites of the general formula VI.
  8. Method for purifying racemic, R- or S-thioctic acid or mixtures thereof by the action of sulphites of the general formula VI, optionally in the presence of inert solvents, on the crude products dissolved in dilute alkali solutions.
EP03729427A 2002-01-16 2003-01-07 Method for producing thioctic acid Expired - Lifetime EP1467983B1 (en)

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DE10201464A DE10201464B4 (en) 2002-01-16 2002-01-16 Process for the preparation of pure thioctic acid
DE10201464 2002-01-16
PCT/EP2003/000064 WO2003059902A1 (en) 2002-01-16 2003-01-07 Method for producing thioctic acid

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ITMI20050466A1 (en) * 2005-03-22 2006-09-23 Laboratorio Chimico Int Spa PURIFICATION PROCESS IN WATER OF TIOTIC ACID
US20090078581A1 (en) * 2007-09-24 2009-03-26 Applied Intellectual Capital Configurations and Methods of Reduction of Lipoic Acid
BRPI0916476A2 (en) * 2008-12-01 2016-02-16 Invasc Therapeutics Inc composition, treatment method for a renin-angiotensin-aldosterone system-related disorder, method for reducing insulin resistance, method for treating a metabolic syndrome-related disorder
JP2013155145A (en) * 2012-01-31 2013-08-15 Sumitomo Seika Chem Co Ltd Method of producing cyclic disulfide compound
CN105524040A (en) * 2016-02-19 2016-04-27 苏州富士莱医药股份有限公司 Preparation method of (R)-(+)-lipoic acid
CN105622571A (en) * 2016-03-08 2016-06-01 苏州富士莱医药股份有限公司 Preparation method of R-lipoic acid tromethamine salt
CN112480065A (en) * 2020-12-15 2021-03-12 苏州富士莱医药股份有限公司 Preparation method of lipoic acid impurity
CN113292533B (en) * 2021-05-25 2024-04-16 四川智强医药科技开发有限公司 Method for purifying polymer impurities in lipoic acid
CN114149324B (en) * 2021-12-07 2023-08-22 厦门金达威维生素有限公司 Synthesis method of 6-hydroxy-8-chlorooctanoic acid ethyl ester, 6, 8-dichloro octanoic acid ethyl ester and lipoic acid
CN116496245A (en) * 2023-03-01 2023-07-28 杭州新曦科技有限公司 Process for preparing R-alpha-lipoic acid and related intermediates thereof

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AU2003210152A1 (en) 2003-07-30
WO2003059902A1 (en) 2003-07-24
DE10201464B4 (en) 2005-06-16
ES2260625T3 (en) 2006-11-01
ATE322489T1 (en) 2006-04-15
DK1467983T3 (en) 2006-08-07
EP1467983A1 (en) 2004-10-20
US20050107620A1 (en) 2005-05-19
PT1467983E (en) 2006-08-31
US7208609B2 (en) 2007-04-24

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